Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis

Iodice, Carmela; Balletta, M; Minutolo, Roberto; Giannattasio, Paolo; Tuccillo, S; Bellizzi, Vincenzo; D’Amora, Maurizio; Rinaldi, Giorgio; Signoriello, Giuseppe; Conte, Giuseppe; Nicola, Luca De

doi:10.1046/j.1523-1755.2003.00015.x

Cited by 35 publications

(29 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, those using relatively high doses of ACEi and ARB failed to observe additive effects, such as observed in 5/6 nephrectomized rats and ADR-induced glomerulopathy [21, 34]. Similarly, in humans, combination of rather low doses of ACEi and ARB resulted in a more pronounced renoprotection than the use of either drug alone in non-diabetic proteinuric nephropathies [8, 9, 10], whereas the combined therapy did not improve the renal function than the use of ACEi or ARB alone of higher doses [6, 7]. In fact, another study also suggested that optimal antiproteinuric dose of either drug alone by dose-titration should be established before examining the effect of combination therapy of ACEi and ARB [35].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the effectiveness of dual RAS blockade with both ACEi and ARB has not been established. Studies revealing a lack of any additive effects of the combination therapy in humans used the maximal or nearly maximal doses of either ACEi or ARB [6, 7], whereas others showing additive antiproteinuric effects used the combination of lower or halved doses of ACEi or ARB [8, 9, 10]. …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combined Therapy of Cilazapril and Losartan Has No Additive Effects in Ameliorating Adriamycin-Induced Glomerulopathy

Kim¹,

Ryu²,

Han³

et al. 2004

Nephron Physiol

View full text Add to dashboard Cite

Aims: Effects of the blockade of renin-angiotensin system (RAS), by angiotensin-converting enzyme inhibitor (ACEi), type 1 angiotensin II receptor blocker (ARB), or a combination of both, were evaluated in Adriamycin (ADR)-induced glomerulopathy. Methods: Male Sprague-Dawley rats (180–250 g) were induced of glomerulopathy by treatment with ADR (2 mg/kg, i.v.). Six weeks later, they were treated with cilazapril (1 mg/kg/day) and/or losartan (10 mg/kg/day) for an additional 6 weeks. Results: The urinary excretion of protein progressively increased following the treatment with ADR, which was prevented by ACEi, ARB, and a combination of both. Similarly, the glomerulopathy assessed by glomerulosclerosis index was also ameliorated by ACEi or ARB. However, combined therapy of both ACEi and ARB was without an additional effect (Control 1.4 ± 0.4%, ADR 10.7 ± 2.7%**, ACEi 0.8 ± 0.4%, ARB 2.6 ± 1.0%, ACEi+ARB 1.7 ± 1.5%, ** p < 0.01 vs. Control). The expression of transforming growth factor-β₁ was increased following the treatment with ADR (1.4 ± 0.07-fold, p < 0.05 vs. Control), however, the degree of which was similarly blunted by either ACEi, ARB, or the combination of both. The expression of type 1 angiotensin II receptor mRNA increased following the treatment with ADR, the degree of which was further upregulated by ACEi and decreased by ARB to the control level (ADR 1.3 ± 0.06-fold*, ACEi 1.8 ± 0.05-fold***, ARB 1.0 ± 0.04-fold, * p < 0.05 and *** p < 0.001 vs. Control). The combined therapy of ACEi and ARB still showed an upregulation of type 1 angiotensin II receptor mRNA, however, of which degree was mitigated compared with that induced by ACEi alone (ACEi+ARB 1.5 ± 0.04-fold, ** p < 0.01 vs. Control). On the contrary, the expression of type 2 angiotensin II receptor mRNA was downregulated following the treatment with ADR, which was similarly restored to the control level by ACEi, ARB, and a combination of both (ADR 0.5 ± 0.08-fold**, ACEi 1.0 ± 0.06-fold, ARB 1.0 ± 0.05-fold, ACEi+ARB 1.0 ± 0.05-fold, ** p < 0.01 vs. Control). Conclusion: It is suggested that combined therapy of ACEi and ARB with relatively high or maximal doses of each drug has no additive or synergistic benefits on the progression of ADR-induced glomerulopathy. Effects of RAS blockade may in part be related to differential regulation of type 1 and type 2 angiotensin II receptors.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combined Therapy of Cilazapril and Losartan Has No Additive Effects in Ameliorating Adriamycin-Induced Glomerulopathy

Kim¹,

Ryu²,

Han³

et al. 2004

Nephron Physiol

View full text Add to dashboard Cite

show abstract

“…Antiproteinuric and renoprotective effects of ACEI have been shown with four different ACEI (captopril, enalapril, benazepril, and ramipril) used in relatively low doses (78). High-dose ACEI therapy may be more antiproteinuric and more renoprotective than usual doses (4,72,79 -81), although mild anemia has been reported with ramipril at 20 mg daily (82). Current trends are to use the maximum recommended dose of ACEI, if tolerated (4,11,72,79 -81).…”

Section: Acei Therapy (Level 1)mentioning

confidence: 99%

Management of Glomerular Proteinuria

Wilmer¹,

Rovin²,

Hébert

et al. 2003

Journal of the American Society of Nephrology

188

120

View full text Add to dashboard Cite

show abstract

“…Clinical and experimental studies have identified the reninangiotensin system as a key factor in development and progression of glomerular diseases (1)(2)(3). A chronically enhanced effect of the renin-angiotensin system is a central event in the development of proliferative and sclerosing changes in the glomeruli.…”

mentioning

confidence: 99%

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

Yano

Suzuki

Endoh

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Chronic activation of the angiotensin II (ANG II) type 1 receptor (AT-1R) is critical in the development of chronic kidney disease. ANG II activates mesangial cells (MCs) and stimulates the synthesis of extracellular matrix components. To determine the molecular mechanisms underlying the induction of MC collagen, a mouse mesangial cell line MES-13 was employed. ANG II treatment induced an increase in collagen synthesis, which was abrogated by cotreatment with losartan (an AT-1R antagonist), wortmannin (a phosphoinositide 3-kinase (PI3K) inhibitor), an Akt inhibitor, and stable transfection of dominant negative-Akt1. ANG II induced a significant increase in PI3K activity, which was abolished by co-treatment with losartan or 2,5-dideoxyadenosine (2,5-DOA, an adenylyl cyclase inhibitor) but not by PD123319 (an AT-2R antagonist) or H89 (a protein kinase A (PKA) inhibitor). The Epac (exchange protein directly activated by cAMP)-specific cAMP analog, 8-pHPT-2-O-MecAMP, significantly increased PI3K activity, whereas a PKAspecific analog, 6-benzoyladenosine-cAMP, showed no effect. The ANG II-induced increase in PI3K activity was also blocked by co-treatment with PP2, an Src inhibitor, or AG1478, an epidermal growth factor receptor (EGFR) antagonist. ANG II induced phosphorylation of Akt and p70S6K and EGFR, which was abrogated by knockdown of c-Src by small interference RNA. Knockdown of Src also effectively abolished ANG II-induced collagen synthesis. Conversely, stable transfection of a constitutively active Src mutant enhanced basal PI3K activity and collagen production, which was abrogated by AG1478 but not by 2,5-DOA. Moreover, acute treatment with ANG II significantly increased Src activity, which was abrogated with co-treatment of 2,5-DOA. Taken together, these results suggest that ANG II induces collagen synthesis in MCs by activating the ANG II/AT-1R-EGFR-PI3K pathway. This transactivation is dependent on cAMP/Epac but not on PKA. Src kinase plays a pivotal role in this signaling pathway between cAMP and EGFR. This is the first demonstration that an AT1R-PI3K/ Akt crosstalk, along with transactivation of EGFR, mediates ANG II-induced collagen synthesis in MCs.Clinical and experimental studies have identified the reninangiotensin system as a key factor in development and progression of glomerular diseases (1-3). A chronically enhanced effect of the renin-angiotensin system is a central event in the development of proliferative and sclerosing changes in the glomeruli. The octapeptide hormone angiotensin II (ANG II), 2 the major renin-angiotensin system effector, activates mesangial cells (MCs) and increases the synthesis of extracellular matrix components, including collagens, which is a hallmark of the glomerular diseases (4, 5). The physiological functions of ANG II are mediated by at least two structurally and pharmacologically distinct seven-transmembrane helices G protein-coupled receptors (GPCRs), ANG II type 1 and 2 receptors (AT-1R and AT-2R). Glomerular cells, including MCs, express primarily the AT-1R, ...

show abstract

Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis

Cited by 35 publications

References 29 publications

Combined Therapy of Cilazapril and Losartan Has No Additive Effects in Ameliorating Adriamycin-Induced Glomerulopathy

Combined Therapy of Cilazapril and Losartan Has No Additive Effects in Ameliorating Adriamycin-Induced Glomerulopathy

Management of Glomerular Proteinuria

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

Contact Info

Product

Resources

About